Scalable Synthesis of Positively Charged Sequence-Defined

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Scalable Synthesis of Positively Charged Sequence-Defined Functional Polymers Bo Zhao, Zhengguo Gao, Yaochen Zheng, and Chao Gao J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00172 • Publication Date (Web): 05 Mar 2019 Downloaded from http://pubs.acs.org on March 5, 2019

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Journal of the American Chemical Society

Scalable Synthesis of Positively Charged Sequence-Defined Functional Polymers Bo Zhao†, Zhengguo Gao†,‡, Yaochen Zheng‡, and Chao Gao*,† †MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, P. R. China. ‡Department of Polymer Science and Engineering, College of Chemistry and Chemical Engineering, Yantai University, 30 Qingquan Road, Yantai 264005, P. R. China Supporting Information Placeholder ABSTRACT: Synthesizing and characterizing sequence-defined polymers with positively charged backbone are great challenges. By alternately processing Menschutkin reaction and Cu-catalyzed azide-alkyne cycloaddition reaction, we successfully synthesized series of scalable cationic sequence-defined polymers with quaternary ammonium backbone up to 12 repeating units and characterized their precise structures. Due to the dramatic polarity difference between weak polar feed molecules and strong polar target molecules, simple precipitation in weak polar solvents is enough to obtain pure sequence-defined polymers. Such a polar-inverse strategy (PIS), without protecting groups and solid support, offers extremely high yields up to 68% after 12 reaction steps (i.e., average yield > 95% for each step), favoring cost-effective large-scale production. Because of the independent reactivity of selected functional groups, the cationic sequence-defined polymers are highly programmable, including backbone composition, sequence order, functional side groups, terminal groups and topological structure. Sequence information decoding is easily achieved according to Maldi-Tof mass spectrum without retrospect to its synthetic history, resulting in a great superiority in the field of information transmitting and reading. The resulting multifunctional sequence-defined polymers are water-soluble and positively charged, opening the avenue to bio-applications such as condensing DNA, gene transfection, and drug delivery.

Driven by the goal of imitating biomacromolecules with precisely designed sequences, monodispersity and large chemical diversity, chemists have made great progress in synthesizing artificial sequence-defined polymers in the past decades.1-4 Varieties of synthetic strategies have been created, such as iterative exponential growth strategies,5-10 single unit monomer insertion methods11-17 and stepwise iterative approaches.18-22 Different aspects of properties have been in-depth studied, for instance, information coding/decoding,23-28 structural characters29-33 and biological properties.33-35 Among previous reports, most of the existing artificial sequence-defined polymers are uncharged, part polymers with polyphosphate backbone are negatively charged,23, 36 and a few polymers have secondary amine or tertiary amine backbone.37 To date, no report on synthesizing monodisperse polymers with positively charged backbone of quaternary ammonium has been

published, mainly due to the difficulties of molecular design, synthesis, and characterization. The cationic backbone offers water-soluble property, resulting in a great advantage in bio-applications compared with existing water-insoluble sequence-defined polymers.38-40 Furthermore, well-defined cationic polymers can precisely interact with negatively charged DNA and siRNA, leading to a controllable effect in gene transfection and drug delivery. Therefore, synthesizing cationic sequence-defined polymers is of great significance. Here we developed a new polar-inverse strategy (PIS) for scalable synthesizing sequence-defined polymers with positively charged backbone by alternately processing Menschutkin reaction and Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Polymers with up to 12 positive ions and 4800 Da were synthesized and characterized. Employing six different side group functionalized monomers and three different starting units, eight series of polymers with different sequence orders were synthesized in high yields. The sequence information was decoded in a very efficient way. Figure 1 shows the structures of monomers (M1-M6, nitrine-tertiary amines) and an adapter unit (X, propargyl bromide) used in the synthetic route of PIS method. Menschutkin reaction is a viable reaction to generate onium ions from uncharged monomers. Big polarity difference between the uncharged monomers and cationic target polymers results in high solubility difference in weak polar solvent. Thus, simple precipitation in diethyl ether is enough to obtain pure sequence-defined polymers, rather than solid-phase purification that is widely employed in previous reports. Typically, starting unit S1 reacts with adapter X via Menschutkin reaction mechanism to get X-S1-X with two cationic ions and two alkynyl groups. Monomer M1 further reacts with X-S1-X via CuAAC process to achieve M1X-S1-XM1 with two cationic ions and two tertiary amino groups. Repeating Menschutkin reaction with X followed by CuAAC with M1 gives birth to target cationic sequence-defined polymers (M1X)n-S1-(XM1)n, wherein n is the repeating times. In our PIS method, the starting unit, adapter and monomer can be well designed and altered, and the side and terminal groups can be defined. Since the stabilisation of the LUMO (lowest unoccupied molecular orbital) of electrophile and the strong

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Figure 1. Synthesis of positively charged sequence-defined polymers. (a) Structures of monomers with different side groups: M1 (hydrogen), M2 (ethyl), M3 (dimethyl), M4 (alkenyl), M5 (phenyl), M6 (benzyl). (b) Stepwise iterative reactions for synthesizing bidirectional sequence-defined polymers. (i) DMF, propargyl bromide, room temperature, 4 hours; (ii) DMF, CuBr, nitrogen atmosphere, 40 °C, 4 hours. (c) Synthesis of sequence-defined polymers with different side chains, topological structure and terminal groups.

electron-withdrawing inductive effect caused by α-alkynyl group, Menschutkin click-like reaction between propargyl bromide and tertiary amine group proceeded to completion in less than 4 hours at room temperature in strong polar solvents, such as DMF and DMSO.41 CuAAC click reaction is widely used for synthesizing monodisperse polymers.42-44 In our method, it is also a 100% complete reaction. As a result, no polymers with lower generation remain in the product after each step, and no more purification, like column chromatography, is required, leading to an extremely high yields. In this work, the yield reached 68% in gram-scale after growing 12 repeating units, indicating the possibility in even larger scale synthesis (Figure S53). Since the monomer has a tertiary amine group itself, no more extra ligand, such as PMDETA, was needed during the CuAAC reaction. Residual Cu

catalyst was eliminated from the final product by the established method.45 For the purpose of extending chemical diversity, different side groups were imported into the monomers of nitrine-tertiary amines by two-step esterification reaction (Scheme S1-5). Here, monomers with ethyl, dimethyl, phenyl, benzyl and reactive alkenyl side groups were synthesized and characterized (M1-M6, Figures S1-S12). Different monomers can be designed by this method with desired functional side groups. Similar to natural polypeptides defined by amino acids with independently functionalized side chains, the presented polymers are also precisely designed with discretionary side group sequences such as alkenyl. The alkenyl side group of M4 has independent


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Journal of the American Chemical Society reactivity and can be further functionalized with other groups, such as 1-thioglycerol either in monomer or polymers (Scheme S6). With different starting unit, such as N, N, N', N' -tetramethylethylenediamine (S1), N, N-dimethylethanolamine (S2) and triethylamine (S3), cationic sequence-defined polymers with different topological structures and terminal groups were easily synthesized using PIS method (Figure 1c). All the measurements indicated that different end group or topological structure did not affect the step growth (Figure 2, 3, S13-23). Importing independently reactive terminal group makes sequence-defined polymers more adjustable and highly potential for chemistry tailoring and applications. Furthermore, the number of atoms between positive ions in the backbone can also be controlled by designing monomers, which makes it feasible to adjust the interaction between the cationic sequence-defined polymers and DNA or siRNA with negatively charged backbone.

Size-exclusion chromatography (SEC) characterization with water mobile phase for positively charged polymers has been a big challenge in the past years, since cationic polymers have a strong adsorption effect to chromatographic column which leads to no analyzable signal output.46 To address this problem, we found a water phase chromatographic column filled with positively charged stuffing which has a strong repulsion effect to cationic polymers to counteract the adsorption, leading to a visible monodisperse peak. Consequently, all polymers dissolved in water showed a single peak with polydispersity index (PDI) less than 1.05 (Figure 2, 3). Mass spectrum measurement for cationic polymers is also a big challenge, and almost no report on measuring polymers with positively charged backbone has been published.47 In our case, polymers with multiply bromine anions gave no analyzable peak in all kinds of mass spectra, mainly caused by the instability of the quaternary ammonium bond and the tendency to form multiply charged fragments while characterizing. For increasing stability of onium ions to observe molecular ion peak and single charged fragment peaks clearly in matrix-assisted laser desorption/ionization time of flight mass spectrometry (Maldi-Tof MS), we employed lithium bis(trifluoromethane sulfonimide) (LiTf2N) to exchange the bromide anions of polymers. In subsequent Maldi-Tof MS measurements, the molecular ion peak ([Px+[Tf2N-]x-1]+, wherein P represents the main part of polymer) of each sequence-defined polymer and fragment peaks caused by rupture of quaternary ammonium bond were observed clearly (Figure 2, 3, S24-50). Meanwhile, concomitant peaks were observed at m/z smaller than the main peaks by 127.03 due to ion exchange between the polymer and the matrix (i.e., 2, 5-dihydroxybenzoic acid (DHB)) in Maldi-Tof MS, forming fragments of [Px+[Tf2N-]x-2[DHB-]]+. With increasing molecular weight and number of positive ions, the molecular ion peak became gradually weaker, and finally reached a detection limit at about 4500 Da with 8 positive ions. Although polymers with more onium ions cannot be measured by Maldi-Tof MS, SEC measurement is still workable. PDI of the resulting polymer with 12 constitutional units on both sides is still very narrow (< 1.05), demonstrating its monodispersity (Figure 2). Table 1. Maldi-Tof MS characterization of positively charged sequence-defined polymers. No. P1

Sequence (M1X)4-S1-(XM1)4

m/zcal 4452.81

m/zexp 4455.43

Yield 68%[a]

P2

M6XM4XM1X-S1-XM1XM4XM6

3678.86

3680.01

75%

P3

S2-XM1XM4XM3XM6

2335.59

2336.66

70%

P4

M6XM6XM6X-S1-XM6XM6XM6

4019.00

4019.58

75%

P5

S2-XM1XM2XM2XM4

2243.57

2244.60

82%

P6

S2-XM1XM3XM1

1568.42

1568.45

76%

P7

S2-XM6XM5XM2

1794.52

1795.25

80%

P8

S3-XM1XM2XM2

1608.49

1609.30

81%

Measured in positive ion mode [a]: Yield for (M1X)6-S1-(XM1)6

Figure 2. Rupture mechanism and SEC traces, Maldi-Tof spectra of the polymer series P1. (a): Rupture of quaternary ammonium bond in Maldi-Tof. (b): Maldi-Tof spectrum for polymer P1 in DHB matrix. (c) SEC curves for polymer series P1. *: Concomitant peak [Px+[Tf2N-]x-2[DHB]-]+, manifested as 127.03 less than the main peak, [Px+[Tf2N-]x-1]+.

To study the law of bond fragmentation in Maldi-Tof MS, polymer with sequence M6XM4XM1X-S1-XM1XM4XM6 (polymer P2 in Table 1) was measured. The molecular ion peak (calculated value 3678.86 and found at 3680.01) is clearly observed, and peaks of its former pre-polymers M4XM1X-S1-XM1XM4 (calculated at 2284.59 and found at 2285.26) and XM4XM1X-S1-XM1XM4X (calculated at 2922.48 and found at 2923.36) are not detected (Table S2), confirming the complete conversion of both Menschutkin and CuAAC reactions.



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Figure 3. SEC traces and Maldi-Tof spectra of the cationic sequence-defined polymers. (a) Maldi-Tof spectrum for polymer P2 in DHB matrix. (b) SEC curves for polymer series P2. (c) Maldi-Tof spectrum for polymer P3 in DHB matrix. (d) SEC curves for polymer series P3. *: Concomitant peak [Px+[Tf2N-]x-2[DHB]-]+, manifested as 127.03 less than the main peak, [Px+[Tf2N-]x-1]+.

During Maldi-Tof measurements, heterolytic cleavage is easy to occur at quaternary ammonium bond, so an uncharged moiety linked at side of α-pyrrodiazole or α-alkynyl, and a positively charged moiety on the other side (Figure 2a) would form due to the strong electron withdrawing effect of α-pyrrodiazole or α-alkynyl group. Single charged second fragmentation peaks are too weak to be detected. For all the polymers synthesized, every single charged fragment peak larger than the lower detection limit was observed (Figures S24-S50, Table S1-S8). The combination of SEC, Maldi-Tof MS, nuclear magnetic resonance (NMR) (Figure S13-23), and infrared (IR) spectroscopy (Figure S52) measurements confirmed the fine structures of cationic functional sequence-defined polymers.

hexadecimal or even more data density can be easily made. Hence, the cationic sequence-defined polymers are excellent information carriers. Besides, the cationic sequence-defined polymers with reactive side chains and terminal groups can be easily modified for applications in gene transfection and drug delivery48-50. By modifying side groups with nucleobases, artificial cationic-DNA can be synthesized.51 Preliminary gene transfection tests were performed with the as-synthesized quaternary ammonium polymers. The results demonstrate that the gene transfection efficiency was highly affected by the molecular weight or number of ammonium indeed, indicating the significance of precise control over cationic molecular structures (Figure S55). The details will be published elsewhere.

Moreover, we studied the decoding method of the cationic polymers by analyzing the Maldi-Tof MS spectra of different sequences (Table S1-S8). According to the fragmentation mechanism, the only two things we need to know for decoding the sequences are the starting unit and monomer alphabet. We can simply ‘read’ the sequence information by calculating the gap between two fragment peaks without recourse to the synthetic history. No complicated algorithm is required and all single-charged fragments result in no deconvolution, leading to a high resolution (Figure S51). The gap between the molecular ion peak and the largest fragment peak gives the information of the last one or two constitutional units, and the next gap represents the former two units, and so on. This decoding method is viable for both monodirectional and bidirectional growth cationic polymers. Herein, we only varied epoxy unit while synthesizing the monomers constructed by three parts (Scheme S1-5), and the information density will be exponentially increased if the mass of other two parts is changed. In this case, an alphabet with

In conclusion, we successfully developed a new PIS method to synthesize series of scalable, water-soluble sequence-defined polymers with positively charged quaternary ammonium backbone by alternately processing Menschutkin and CuAAC reaction. The versatile synthetic strategy is viable for diverse structure design, such as different side groups, sequence order, starting unit, terminal group, negative ion and topological structure. High yield and simple reaction condition without solid support or protecting groups offer the possibility of automatic production in large-scale. Distinct molecular ion peak and fragment peaks in Maldi-Tof MS provide an easy way to decode the sequence information without recourse to its synthetic history or deconvolution. Such a performance gives a great superiority in information transfer and reading with high data density and high resolution. The PIS enables cost-effective large-scale production of multifunctional sequence-defined polymers, paving the way to their applied research and real applications.

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Journal of the American Chemical Society Supporting Information Synthetic procedures, experimental methods.

characterization

data,

photos

and

AUTHOR INFORMATION Corresponding Author *[email protected]

Author Contributions Bo Zhao and Zhengguo Gao contributed equally.

ACKNOWLEDGMENT This work is supported by the National Natural Science Foundation of China (No. 51533008), National Key R&D Program of China (No. 2016YFA0200200), Fujian Provincial Science and Technology Major Projects (No. 2018HZ0001-2), and the Fundamental Research Funds for the Central Universities (No. 2017XZZX001-04).

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Journal of the American Chemical Society

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Scalable Synthesis of Positively Charged Sequence-Defined

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